THERAPEUTIC DRUG MONITORING AND EVALUATION OF SAFETY OF INTRAVENOUS INFUSION OF AMIKACIN IN PATIENTS WITH CYSTIC FIBROSIS

Aleksandar Nikodinovski; Stojka Naceva Fushtikj; Jasmina Trojacanec; Krume Jakjovski; Bojan Labacevski; Nikola Kolovcevski; Marija Perkovikj Bujaroska; Zorica Bozhinoska; Dijana Grupche; Nikola Labacevski

Aleksandar Nikodinovski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Stojka Naceva Fushtikj JZU University Clinic of Pediatric Diseases, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Jasmina Trojacanec Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Krume Jakjovski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Bojan Labacevski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Nikola Kolovcevski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Marija Perkovikj Bujaroska Institute of Forensic Medicine, Criminology and Medical Deontology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Zorica Bozhinoska Institute of Forensic Medicine, Criminology and Medical Deontology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia
Dijana Grupche General hospital Ohrid, Ohrid, North Macedonia
Nikola Labacevski Department of Preclinical and Clinical Pharmacology and Toxicology, Faculty of Medicine, Ss.Cyril and Methodius University in Skopje, North Macedonia

Abstract

Therapeutic drug monitoring (TDM) involves measuring drug concentrations in plasma, serum or blood. This information is used to individualize dosage so that drug concentrations can be maintained within a target range and to make dose adjustments. Amikacin is a kanamycin-derived semisynthetic aminoglycoside antibiotic and one of the important antimicrobial agent against Gram-negative pathogens. Aminoglycoside antibiotics have a small therapeutic index and therapeutic range due to monitoring of amikacin concentrations is necessary. For optimal antimicrobial effect of amikacin therapy and prevent toxicity, it is recommended monitoring of amikacin concentrations during therapy with this drug. The study for evaluation of safety of the therapy with amikacin intravenous infusion included 12 patients (7 male and 5 female) with cystic fibrosis. Amikacin was infused over 1 h in the dose of 30 mg/kg (maximum 1.5 g) one time daily during 10-14 days. Blood samples for determination concentrations of amikacin were obtained at the following times: immediately before administration of third dose of amikacin, at the end of infusion, 30 min. and 6 h after infusion. The concentrations of amikacin in the sample before administration of third dose of amikacin was <2 Âµg/ml in all treated patients. Safety of the therapy was evaluated from the results of laboratory analyses, creatinine clearance (estimated according to the Cockroft-Gault equation), anamnestic symptoms of ototoxicity or vestibular toxicity, evaluation of the whisper test and other adverse events. From the results of our study, we suggest that the dose of 30 mg/kg once daily amikacin infusion administered for 10-14 days is safety in patients with cystic fibrosis.

Key words: amikacin, therapeutic drug monitoring (TDM), cystic fibrosis, intravenous infusion, safety, creatinine clearance (CCr), ototoxicity, vestibular toxicity.

References

1. Kang JS and Lee MH: Overview of Therapeutic Drug monitoring. Review. DOI: 10.3904/kjim.2009.24.1.1.
2. Ghiculescu RA: Therapeutic Drug monitoring: which drugs, why, when and how to do it. Aust Prescr 2008, 31:42-44.
3. Xu L, Cheng X, Guanhua Z, Hu J, Li Q, Fan G: Therapeutic Drug monitoring of amikacin: quantification in plasma by liquid chromatography-tandem mass spectrometry and work experience of clinical pharmacists. Eur J Hosp Pharm 2022, e77-e82.doi:10.1136/ejhpharm-2021-003-049.
4. Zylbersztajn B, Barraza M, Torres JP, Morales J: Therapeutic monitoring of antimicrobial agents un pediatrics. Review based on Latin American experiences. Rev.chil.infectol. 2018, vol 35 (1).
5. Pacifici GM and Marchini G: Clinical Pharmacology of amikacin in infants and children. Clin Med Invest 2020, 5:1-14. doi:10.15761/CMI.1000199.
6. Jenkins A, Thomson HA, Brown MN, Semple Y, Sluman C, MacGowanA, Lovering MA and Wiffen JP: Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affects either outcome or adverse events? A systematic review. J.Antimicrob Chemother 2016, 71:2754-2759.
7. Amikacin 250 mg/ml & 500 mg/ml SmPC: https://www.medicines.org.uk/emc/ product/3784/smpc #gref.
8. Sumpter A, Anderson BJ: Pediatric Pharmacology in the first year of life. Curr. Opin. Anesthesiol. 2009, 22(4):469-475.
9. Zaske D.: Applied Pharmacokinetics. Principles of therapeutic Drug Monitoring. 3rd ed.Vancouver: Applied Pharmacokinetics:1992.
10. Toit M, Burger JR, Rakumakoe MD and Rheeders M: Standars of aminoglycoside therapeutic drug monitoring in a South Africa private hospital: perspectives and implications. Ghana Med J:2019, 53(1):8-12.
11. Lenoir M, Puel J.: Dose dependent changes in the rat cochlea following aminoglycoside intoxication. II. Histological study : Hear Res 1987; 26:199-209.
12. Abdul -Aziz HM : Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper. Intensive Care Med 2020, 46:1127-1153.
13. Buclin T, Thoma Y, Widmer N, Andre P, Guidi M, Csajka C, Decosterd AL: The steps to Therapeutic Drug Monitoring: A structured Approach Illustrated with Imatinib. Front Pharmacol 2020, https://doi.org/10.3389/fphar.202000177.
14. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron, 1976; 16:31-41.
15. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146â€“55.doi: 10.1378/chest.118.1.146.
16. Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med. 1998;244:379â€“86.doi: 10.1046/j.1365-2796.1998.00379.x.
17. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a riskfactor for hospital mortality among critically ill patients. Chest. 1999;115:462â€“74.doi: 10.1378/chest.115.2.462.
18. Fraser A, Paul M, Almanasreh N, Tacconelli E, Frank U, Cauda R, et al. Benefit of appropriate empirical antibiotic treatment: thirty-day mortality and duration of hospital stay. Am J Med.2006;119:970â€“6. doi: 10.1016/j.amjmed.2006.03.034.
19. Franson TR, Quebbeman EJ, Whipple J, Thomson R, Bubrick J, Rosenberger SL, et al. Prospective comparison of traditional and pharmacokinetic aminoglycoside dosing methods. Crit Care Med.1988; 16:840â€“3. doi: 10.1097/00003246-198809000-00004.
20. Bartal C, Danon A, Schlaeffer F, Reisenberg K, Alkan M, Smoliakov R, et al. Pharmacokinetic dosing of aminoglycosides: a controlled trial. Am J Med. 2003; 114:194â€“8. doi: 10.1016/S0002-9343(02)01476-6.
21. DeMaria A, Jr, Treadwell TL, Saunders CA, Porat R, McCabe WR. Randomized clinical trial of aztreonam and aminoglycoside antibiotics in the treatment of serious infections caused by gram-negative bacilli. Antimicrob Agents Chemother. 1989;33:1137â€“43. doi: 10.1128/AAC.33.8.1137.
22. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS., Jr Optimizing aminoglycoside therapy fornosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother.1999;43:623â€“9.